Voices of hope and determination: people with MS impact Tysabri recommendation.

"It was a really scary experience, but incredibly empowering," said MRI technologist Barbara Crooks, who was diagnosed with MS eight years ago. Crooks was one of more than three dozen people who testified during the public discussion session of the two-day FDA Advisory Committee meeting on Tysabri that began March 7, 2006.

"The energy was electrifying," Crooks said. "There were more than 40 people testifying, and another 200 in the audience. I felt we (people with MS) were very well represented. There were nurses, teachers, and doctors. There was a nuclear physicist, a preacher and his wife, countless moms, and the family of Anita Smith, who died from PML. There were representatives of health organizations and advocacy groups. There were people with 'invisible symptoms' and video testimony from people who were quadriplegic."

The FDA expanded the committee meeting from one to two days in response to pressure from the Society and people with MS because so many people wanted to voice their opinions about Tysabri.

"The panel was very welcoming to our views and made me feel very comfortable," Crooks continued. "People from all over the country came out and our voices were heard."

The open public discussion followed a presentation by FDA officials and reviews by Biogen Idec and Elan Pharmaceuticals, Inc., of study data and the Tysabri Risk Management Action Plan. (See "Estimating--and minimizing--risk," page 30.)

The National MS Society's role

Advocating on behalf of people with MS and their families, the National MS Society took an unprecedented leadership role, working with the FDA.

"The Society made recommendations to the FDA concerning the experts best qualified to serve on the advisory panel," said John Richert, MD, vice president of Research and Clinical Programs for the Society. "We urged the FDA to support a thorough and inclusive review of the drug's risks and benefits and we advocated for the speediest possible review."

Society gives voice to people with MS

The Society Web site and its network of chapters provided ongoing information on Tysabri, beginning with the initial release and through its withdrawal, maintaining a live link from the national Web site to the FDA for anyone interested in having personal views heard by the advisory committee.

In December 2005, the Society commissioned an independent national survey of more than 800 people with MS about Tysabri, safety concerns, and choice.

Joyce Nelson, president and CEO of the Society, elaborated on the Society's role: "The FDA's decision will affect each and every person with MS. These are the people who live with the disease every single day of their lives. It was crucial that they were considered in the decisionmaking process. We wanted to shine light on the issues they say are most important to them," Nelson said.

The survey, conducted by International Communications Research and Harris Interactive Service Bureau, asked dozens of questions, including: "How would you describe your overall opinion of Tysabri?" and "Do you think that Tysabri should be made available again?"

Opinions about the drug ranged from very positive to very negative. Half of the respondents had no definite opinion as to whether the drug should be returned to the market and wanted more information before making a decision. Most people said that they would consider using Tysabri under certain conditions, especially if their current treatment was not working well. They wanted access to a reliable test for PML and additional safety data.

Estimating--and minimizing--risk

No one knows the true risk of developing PML. A report on the cases of PML within the Tysabri trials was published in the March 2, 2006, issue of The New England Journal of Medicine. The researchers estimated that the incidence of PML in people who received Tysabri in the three clinical trials, taking an average of 17.9 monthly doses, is 1 case per 1000 patients.

Biogen Idec and Elan Pharmaceuticals, Inc., have proposed a risk management action plan, careful tracking of any adverse events, and a 5,000-person observational study to help evaluate long-term safety.

The FDA may require a "black box" warning on Tysabri's packaging as a condition for approval. A black box label is the strongest warning the FDA can impose on a pharmaceutical. Black boxes can be found on many other drugs, including the anti-depressant Prozac, Celebrex for arthritis, and eczema creams like Protopic.

The choice to take a therapy with a black box warning is a personal issue, and the individual's risk-to-benefit ratio must be carefully considered in consultation with a qualified medical professional.

The Tysabri story

In November 2004, the FDA granted accelerated approval of Tysabri (natalizumab) for treatment of relapsing forms of MS, creating a new treatment option. The approval was based on 1-year data from two 2-year trials. In the first trial, AFFIRM, Tysabri reduced the frequency of relapses by 68% relative to placebo; in the second trial, SENTINEL, a combination of Tysabri and Avonex (interferon beta-1a) reduced relapse rates by 54% relative to Avonex alone.

But two people receiving the drug in the SENTINEL trial developed progressive multifocal leukoencephalopathy or PML. One of them died and the other remains significantly disabled. A third case of PML was later confirmed in a person who had been taking the drug in a trial for Crohn's disease. That person also died. Tysabri was immediately taken off the market.

Since then, Tysabri's sponsors Biogen Idec and Elan Pharmaceuticals, Inc., conducted safety reviews of the vast majority of the 3,000 people involved in Tysabri trials for MS, Crohn's disease, and rheumatoid arthritis. In September 2005, they submitted the results, requesting that the FDA conduct a "priority review" of their new data. Last November, the FDA agreed.

On March 8, 2006, the FDA's Advisory Committee unanimously recommended that Tysabri be returned to market for relapsing forms of MS, The committee also voted 7 to 5 to recommend Tysabri as a "first-line" therapy. In other words, Tysabri should be available to people who have not tried any of the other disease-modifying drugs (Avonex, Rebif, Betaseron, or Copaxone). The committee recommended against limiting access to Tysabri based on disability level.

While the FDA is not required to follow the recommendations of its advisory committee, it usually does. The FDA was expected to make a decision about Tysabri by the end of March, after this issue went to press. For the latest news, consult our Web site, nationaimssociety.org/tysabri, or call your chapter at 1-800-FIGHT-MS.

How Tysabri works

Tysabri (natalizumab) is a monoclonal antibody that blocks adhesion molecules" on the surface of immune cells. Research suggests that the drug prevents immune cells from sticking to capillary walls and then migrating from the bloodstream into the brain and spinal cord. There, these cells can cause inflammation and start the process that damages nerve fibers and the myelin that insulates them. Tysabri is delivered by I.V. infusion in a health-care facility once a month.

Gary Sullivan is the managing editor of this magazine.